This invention relates to pharmaceutical compositions based on 1,2-bis(3,5-dioxopiperazin-1-yl)-propane and pharmaceutically acceptable salts thereof.
1,2-bis(3,5-dioxopiperazin-1-yl)-propane is of formula 
and it may exist in the d-isomeric form, the 1-isomeric form and in the racemic d1-form.
The racemic d1-form of 1,2-bis(3,5-dioxopiperazin-1-yl)-propane is known as razoxane. Compounds of this kind belong to the family of bis-dioxopiperazines, which have been known for a long time, particularly as anti-tumor agents. This class of compounds, their use and preparation are described in, e.g. GB-A-1 234 935, GB-A-1 374 979, U.S. Pat. No. 4,275,063, EP-A1 491 053, EP-A1 256 137, EP-A1 230 474, EP-A2 014 327 and EP-A1 125 475.
The bis-dioxopiperazines represent lipophilic derivatives of EDTA (ethylene diamino tetraacetic acid), a substance known as a chelating agent. As such they are thought to act by chelating iron, thereby reducing site-specific oxygen radical production. The bis-dioxopiperazines exert topoisomerase II inhibitory activity which presumably is responsible for the antitumor activity of these drugs. The d-enantiomer of razoxane is known as dexrazoxane. The current clinical use of dexrazoxane is to prevent doxorubicin-induced cardiac disease in patients with metastatic breast cancer.
Dexrazoxane is commercially available as the hydrochloride salt. In Europe, dexrazoxane.HCl is available from Chiron, Inc under the registered trade mark Cardioxane, whilst in the US it is available from Pharmacia Upjohn under the registered trade mark Zinecard. A discussion of the chemical, biological and clinical aspects of dexrazoxane and other bis-dioxopiperazines can be found in Current Medicinal Chemistry (1998) 5, 1-28. GB-A-1 234 935 is one of the oldest publications on bis-dioxopiperazines and describes their preparation through cyclisation of the corresponding tetracarboxamidomethyl derivatives through heating together with polyphosphoric acid. The therapeutic spectrum of these drugs includes certain forms of cancer, including leukaemia, and certain non-malignant forms of proliferative disease.
For the preparation of dexrazoxane mainly two methods have been described (U.S. Pat. No. 3,941,790). In the first method 1,2-diaminopropane tetraacetic acid and formamide are heated together to yield the cyclic product. In the second method the corresponding tetraamide of the above tetraacid is heated in polyphosphoric acid or phenol, also leading to cyclisation of the compound (see the previously mentioned GB-A-1 234 935).
Other methods for preparation of dexrazoxane are known, e.g. described in U.S. Pat. No. 4,764,614 or EP-A-0 330 381.
The preparation of a lyophilised composition containing dexrazoxane that is stable and less light-sensitive is described in detail in U.S. Pat. No. 5,760,039.
Psoriasis is a chronic skin disease characterised by scaling and inflammation. The cause of psoriasis is unknown but recent research indicates that it is likely to be an autoimmune disease. Psoriasis is a serious and unpleasant condition which has no cure and not all treatments work for each individual.
Psoriasis can be very painful, but the pain is more than skin deep. The emotions suffer as well. It presents people with physical limitations, disfiguration, and its tedious daily care always demands too much time. Embarrassment, frustration, fear and depression are common. In extreme cases, a loss of self-esteem results in a complete withdrawal from society. Various kinds of temporary relief are available and they work with varying degrees of success. Treatments and medications are often time consuming and expensive but one thing is certain: the symptoms may come and go, but they almost always come again. It is a lifelong disease.
Psoriasis is treated using what is sometimes called the xe2x80x9c1-2-3xe2x80x9d approach. Step 1 is topical treatment, step 2 is phototherapy and step 3 is systemic treatment. Medicines currently prescribed for systemic treatment are the immunosuppressants methotrexate and cyclosporine A, hydroxyurea and retinoids.
Methotrexate and cyclosporine A have unpleasant and potentially dangerous side effects. Moreover, all these treatments leave patients with recurrent psoriasis and because different patients respond differently to varying treatments, it would be very welcome to have additional weapons in the therapeutic armoury.
In 1976, D. J. Atherton (Lancet, ii, 1296, 1976) for the first time proposed the use of racemic razoxane (ICRF-159) for the treatment of psoriasis. A review on the therapeutic use of razoxane in psoriasis can be found in the British Journal of Dermatology (1980) 102, 307. The drug had relatively good efficacy and good tolerability, but some unpleasant side effects and certain toxicities were noticed. Therefore administration of the drug was recommended only under strictly controlled conditions. Horton and Wells (British Journal of Dermatology (1983) 109, 669-673) again reported the relatively good success of treatment with razoxane, however, a considerable proportion of patients stopped treatment because of relatively severe side effects. The most frequently seen side effect was neutropenia, a potentially fatal depletion of neutrophiles (a subset of leukocytes), which was reported to occur in a number of patients even on low doses insufficient to control psoriasis. Other side effects were alopecia, nausea, diarrhoea, nasal bleeding, leg ulceration, lethargy, headaches and squamous epitheliomata.
Because of this and further complications arising after chronic administration, razoxane was not developed further and today is not recommended for treatment of psoriasis. Hitherto, therefore, the known facts about razoxane have been that it cannot be used both safely and effectively to treat psoriasis.
Surprisingly, it has now been demonstrated that the d-enantiomer of 1,2-bis(3,5-dioxopiperazin-1-yl)-propane, dexrazoxane, by itself can be used to treat psoriasis safely and effectively. Indeed, our studies indicate that the treatment results are truly remarkable for some patients, with relief from refractory psoriasis for periods of up to at least one year. No serious side effects have been reported in clinical trials to date, with the vast majority of patients being free of neutropenia and no recorded cases of vomiting, nausea or diarrhoea.
According to the present invention a new pharmaceutical composition for treatment of psoriasis contains as active compound dexrazoxane, or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier and/or excipient.
The invention also includes a method of treating psoriasis in a patient, comprising administering to the patient a therapeutically effective amount of dexrazoxane, the d-isomer of 1,2-bis(3,5-dioxopiperazin-1-yl)-propane, a compound of formula 
or a physiologically acceptable salt thereof.